FoxO1 integrates insulin signaling to VLDL production.
Very low-density lipoproteins (VLDL) are triglyceride-rich particles. VLDL is synthesized in hepatocytes and secreted from the liver in a pathway that is tightly regulated by insulin. Hepatic VLDL production is stimulated in response to reduced insulin action, resulting in increased release of VLDL into the blood under fasting conditions. Circulating VLDL serves as a vehicle for transporting lipids to peripheral tissues for energy homeostasis. Conversely, hepatic VLDL production is suppressed in response to increased insulin release after meals. This effect is critical for preventing prolonged excursion of postprandial plasma lipid profiles in normal individuals. In subjects with obesity and type 2 diabetes, the ability of insulin to regulate VLDL production becomes impaired due to insulin resistance in the liver, resulting in excessive VLDL secretion and accumulation of triglyceride-rich particles in the blood. Such abnormality in lipid metabolism characterizes the pathogenesis of hypertriglyceridemia and accounts for increased risk of coronary artery disease in obesity and type 2 diabetes. Nevertheless, the molecular basis that links insulin resistance to VLDL overproduction remains poorly understood. Our recent studies illustrate that the forkhead transcription factor FoxO1 acts in the liver to integrate hepatic insulin action to VLDL production. Augmented FoxO1 activity in insulin resistant livers promotes hepatic VLDL overproduction and predisposes to the development of hypertriglyceridemia. These new findings raise an important question: Is FoxO1 a therapeutic target for ameliorating hypertriglyceridemia? Here we discuss this question in the context of recent advances toward our understanding of the pathophysiology of hypertriglyceridemia.
Kamagate
Adama
A
Department of Pediatrics, Division of Immunogenetics, Rangos Research Center, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Dong
H Henry
HH
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D002460:Cell Line; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015228:Hypertriglyceridemia / Q000209:etiology / Q000503:physiopathology* / Q000628:therapy; D007328:Insulin / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D001055:Apolipoproteins B; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007328:Insulin; D008079:Lipoproteins, VLDL